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gamma-Hydroxybutyric acid and 5-fluorouracil, metabolites of UFT, inhibit the angiogenesis induced by vascular endothelial growth factor Basaki Y; Chikahisa L; Aoyagi K; Miyadera K; Yonekura K; Hashimoto A; Okabe S; Wierzba K; Yamada YAngiogenesis 2001[]; 4 (3): 163-73UFT, a drug composed of uracil and tegafur at the molar ratio of 4:1, is an orally active agent for the treatment of a wide variety of malignant tumours. Using a murine dorsal air sac (DAS) assay, we have previously shown that UFT and its metabolites, gamma-hydroxybutyric acid (GHB) and 5-fluorouracil (5-FU), inhibited the angiogenesis induced by murine renal cell carcinoma. Here we report that UFT was more effective than other fluorinated pyrimidines such as 5-FU and doxifluridine (5'-DFUR) in blocking the angiogenic responses elicited by five human cancer cell lines which produced high levels of vascular endothelial growth factor (VEGF), but no detectable fibroblast growth factor-2 (FGF-2) in vitro. In contrast, UFT was unable to block the angiogenic response to one human gastric cancer cell line which produced both VEGF and FGF-2 in vitro. However, the production or secretion of VEGF by these cells was unaffected by GHB and 5-FU treatment. Interestingly, GHB suppressed the chemotactic migration and tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by VEGF, without inhibiting their DNA synthesis. Since GHB did not affect the FGF-2-driven activities in HUVECs, its action appears to be VEGF-selective. On the other hand, 5-FU inhibited DNA synthesis and migration of HUVECs stimulated by both VEGF and FGF-2, and tube formation driven by VEGF, suggesting that 5-FU is cytotoxic to endothelial cells. The inhibitory effects of 5-FU, and especially those GHB, were reproduced under in vivo condition using the DAS assay. The VEGF-mediated angiogenesis was significantly inhibited by UFT, 5-FU, and especially by GHB. We propose that the selective inhibitory effects of GHB on VEGF-mediated responses of endothelial cells are involved in the anti-angiogenic activity of UFT.|Angiogenesis Inhibitors/*pharmacology[MESH]|Animals[MESH]|Antimetabolites, Antineoplastic/*pharmacokinetics[MESH]|Breast Neoplasms/metabolism/pathology[MESH]|Carcinoma, Renal Cell/metabolism/pathology[MESH]|Carcinoma/metabolism/pathology[MESH]|Chemotaxis/drug effects[MESH]|Colonic Neoplasms/metabolism/pathology[MESH]|DNA Replication/drug effects[MESH]|Drug Combinations[MESH]|Endothelial Growth Factors/*antagonists & inhibitors/metabolism[MESH]|Endothelium, Vascular/cytology/drug effects[MESH]|Female[MESH]|Fibroblast Growth Factor 2/metabolism[MESH]|Floxuridine/pharmacology[MESH]|Fluorouracil/*pharmacology[MESH]|Humans[MESH]|Intercellular Signaling Peptides and Proteins/metabolism[MESH]|Kidney Neoplasms/metabolism/pathology[MESH]|Lung Neoplasms/metabolism/pathology[MESH]|Lymphokines/*antagonists & inhibitors/metabolism[MESH]|Mice[MESH]|Mice, Inbred BALB C[MESH]|Mice, Inbred ICR[MESH]|Neoplasm Proteins/*antagonists & inhibitors/metabolism[MESH]|Neovascularization, Pathologic/*prevention & control[MESH]|Prodrugs/*pharmacokinetics[MESH]|Prostheses and Implants[MESH]|Recombinant Proteins/antagonists & inhibitors[MESH]|Sodium Oxybate/*pharmacology[MESH]|Stomach Neoplasms/metabolism/pathology[MESH]|Tegafur/*pharmacokinetics[MESH]|Tumor Cells, Cultured/metabolism[MESH]|Uracil/*pharmacokinetics[MESH]|Vascular Endothelial Growth Factor A[MESH]|Vascular Endothelial Growth Factors[MESH]|Xenograft Model Antitumor Assays[MESH] |
